Activation of extracellular signal-regulated kinase is associated with hepatocellular carcinoma with aggressive phenotypes
Takuya Minagawa
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorKen Yamazaki
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorYohei Masugi
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHanako Tsujikawa
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHidenori Ojima
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorTaizo Hibi
Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
Search for more papers by this authorYuta Abe
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHiroshi Yagi
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorMinoru Kitago
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorMasahiro Shinoda
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorOsamu Itano
Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, School of Medicine, International University of Health and Welfare, Chiba, Japan
Search for more papers by this authorYuko Kitagawa
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Michiie Sakamoto
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Correspondence: Professor Michiie Sakamoto, Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected]
Conflict of interest: O.I. carried out joint research with Bayer Pharma AG. The other authors have no conflict of interest.
Search for more papers by this authorTakuya Minagawa
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorKen Yamazaki
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorYohei Masugi
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHanako Tsujikawa
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHidenori Ojima
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorTaizo Hibi
Department of Pediatric Surgery and Transplantation, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
Search for more papers by this authorYuta Abe
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorHiroshi Yagi
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorMinoru Kitago
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorMasahiro Shinoda
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorOsamu Itano
Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, School of Medicine, International University of Health and Welfare, Chiba, Japan
Search for more papers by this authorYuko Kitagawa
Department of Surgery, Keio University School of Medicine, Tokyo, Japan
Search for more papers by this authorCorresponding Author
Michiie Sakamoto
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Correspondence: Professor Michiie Sakamoto, Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected]
Conflict of interest: O.I. carried out joint research with Bayer Pharma AG. The other authors have no conflict of interest.
Search for more papers by this authorAbstract
Aim
Sorafenib inhibits multiple kinase signaling pathways, including the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, and is a promising therapy for hepatocellular carcinoma (HCC). However, the role of ERK activation in HCC remains unclear. This study was designed to investigate the potential link between ERK activation and aggressive HCC phenotypes.
Methods
We evaluated nuclear ERK expression by immunohistochemistry in 154 resected HCC nodules from 136 patients. We then investigated the associations of ERK expression with the clinicopathological characteristics of HCC, c-MET expression, and the molecular subclass biomarkers Ki-67, keratin 19 (KRT19, CK19, or K19), and sal-like protein 4. Multivariate Cox regression analysis was carried out to determine independent prognostic factors for overall survival and recurrence-free survival. The effects of ERK activation by hepatocyte growth factor (HGF) on eight HCC cell lines were further examined.
Results
High-level nuclear expression of ERK was observed in 20 (13%) of 154 nodules and was significantly associated with higher serum alpha-fetoprotein levels (P = 0.034), poorer differentiation (P = 0.003), a higher Ki-67 index (P < 0.001), high-level expression of c-MET (P = 0.008), KRT19 (P = 0.002), or sal-like protein 4 (P < 0.001), and shorter overall survival (multivariate hazard ratio 3.448; P = 0.028) and recurrence-free survival (multivariate hazard ratio 2.755; P = 0.004). HCC cells treated with hepatocyte growth factor showed enhanced cell proliferation together with ERK activation and upregulated KRT19 expression, both of which were inhibited by sorafenib.
Conclusions
High-level ERK activation is associated with a KRT19-positive highly proliferative subtype of HCC with a dismal prognosis. These findings support the key role of the hepatocyte growth factor/c-MET/ERK axis in HCC progression.
Supporting Information
| Filename | Description |
|---|---|
| HEPR13445-sup 0002-suppo S1rev2.tiffTIFF image, 7.5 MB |
Figure S1. Immunohistochemical evaluation of tumor expressions of extracellular signal-regulated kinase (ERK) 1/2 and phosphorylated ERK1/2 (pERK1/2) in hepatocellular carcinoma specimens. |
| HEPR13445-sup 0003-Figure S2.tiffTIFF image, 9.7 MB |
Figure S2. Survival analyses according to c-MET expression. |
| HEPR13445-sup 0004-Figure S3.tiffTIFF image, 6.4 MB |
Figure S3. Relationship between baseline expression levels of phosphorylated of extracellular signal-regulated kinase (pERK) and sensitivity to sorafenib in eight hepatocellular carcinoma cell lines. |
| HEPR13445-sup 0005-Figure S4.tiffTIFF image, 3.4 MB |
Figure S4. Evaluation of expression levels of c-MET and fibroblast growth factor receptor 4 in eight hepatocellular carcinoma cell lines. |
| HEPR13445-supp 0001-Supporting information.docxWord 2007 document , 56.3 KB |
Table S1. Clinicopathological characteristics stratified by c-MET expression levels in 154 hepatocellular carcinoma nodules from 136 patients |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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